Tumor growth is generally limited to 1˜2 mm3 in the absence of a vascularized blood supply, and angiogenesis has a critical role in the invasion, growth and metastasis of tumors (Folkman, J. (2002) Semin. Oncol. 29: 15-8, Folkman, J. (1996) Nat. Med. 2: 167-8, Kerbel and Folkma, (2002). Nature Rev. Cancer. 2: 727-39, Brown et al., (1995) Hum. Pathol. 26: 86-91, Eberhard et al., (2000) Cancer Res. 60: 1388-93). It has been also shown that inhibition of tumor angiogenesis is associated with suppression of tumor progression. In order to achieve suppression of angiogenesis, a number of investigators have been examining therapeutic strategies targeting vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), which play critical roles in regulating the process of angiogenesis. These studies have shown that tumor growth can be successfully suppressed in vitro and in vivo using monoclonal antibodies, recombinant receptors or inhibitors for signal transduction (El-Mousawi et al., (2003) J. Biol. Chem. 278: 46681-91, Stefanik et al., (2001) J. Neurooncol. 55: 91-100, Wood et al., (2000) Cancer Res. 60: 2178-89, Luttun et al., (2002) Nat. Med. 8: 831-40, Lyden et al., (2001) Nat. Med. 7: 1194-201, Lu et al., (2001) Cancer Res. 61: 7002-8). However, these strategies require frequent or continuous administration of the reagents at relatively high dose levels, which may be associated with significant inconvenience and adverse effects.
VEGF binds two related tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR), which are strongly expressed on endothelial cells in tumor tissue but not in normal tissue (Risau, W. (1997) Nature. 386: 671-4, Ferrara and Davis-Smyth, (1997) Endor. Rev. 18: 4-25, Shibuya et al., (1999) Curr. Topics. Microbiol. Immunol. 237: 59-83, Plate et al., (1994) Int. J. Cancer. 59: 520-9). VEGFR1 is the first VEGF receptor to be identified (Shibuya et al., (1990) Oncogene 5: 519-24), and it interacts with VEGF (VEGF-A) and with two other members of VEGF family, VEGF-B (Olofsson et al., (1996) Proc. Natl. Acad. Sci. USA 93: 2576-81) and placenta growth factor (PlGF) (Maglione et al., 1991. Proc. Natl. Acad. Sci. USA 88: 9267-71). By displacing VEGF from VEGFR1, PlGF is expected to make more VEGF available to bind and activate VEGFR2 and thereby enhance VEGF-driven angiogenesis (Park et al., (1994) J. Biol. Chem. 269: 25646-54). Other studies have shown that a synergism exists between VEGF and PlGF in vivo, especially during pathological situations, as evidenced by impaired tumorigenesis and vascular leakage in PlGF−/− mice (Carmeliet et al., (2001) Nat. Med. 7: 575-83).
Recent reports have shown that vaccination using cDNA or recombinant protein of mouse VEGFR2 is associated with significant anti-tumor effects in mouse tumor models (Li et al., (2002) J. Exp. Med. 195: 1575-84, Niethammer et al., (2002) Nat. Med. 8: 1369-75). But these results cannot directly warrant clinical application of this strategy, since they used the mouse homologue of human VEGFR2 in mouse systems that are considered to be significantly different from the human counterpart.